Native language advantage in electrical brain responses to speech sound changes in passive and active listening condition.

It is not clear whether the brain can detect changes in native and non-native speech sounds in both unattended and attended conditions, but this information would be important to understand the nature of potential native language advantage in speech perception. We recorded event-related potentials (ERPs) for changes in duration and in Chinese lexical tone in a repeated vowel /a/ in native speakers of Finnish and Chinese in passive and active listening conditions. ERP amplitudes reflecting deviance detection (mismatch negativity; MMN and N2b) and attentional shifts towards changes in speech sounds (P3a and P3b) were investigated. In the passive listening condition, duration changes elicited increased amplitude in the MMN latency window for both standard and deviant sounds in the Finnish speakers compared to the Chinese speakers, but no group differences were observed for P3a. In passive listening to lexical sounds, P3a was increased in amplitude for both standard and deviant stimuli in Chinese speakers compared to Finnish speakers, but the groups did not differ in MMN. In active listening, both tone and duration changes elicited N2b and P3b, but the groups differed only in pattern of results for the deviant type. The results thus suggest an overall increased sensitivity to native speech sounds, especially in passive listening, while the mechanisms of change detection and attentional shifting seem to work well for both native and non-native speech sounds in the attentive mode.

Distinct biological property of tau in tau-first cognitive proteinopathy: Evidence by longitudinal clinical neuroimaging profiles and compared with late-onset Alzheimer disease.

BACKGROUND: Tau-first cognitive proteinopathy (TCP) denotes a clinical phenotype of Alzheimer disease (AD) showing Florzolotau(18F) positron emission tomography (PET) positivity but a negative amyloid status. AIM: We explored the biological property of tau using longitudinal cognitive and neuroimaging data in TCP and compared with late-onset AD (LOAD). METHOD: We enrolled 56 patients with LOAD, 34 patients with TCP, and 26 cognitive unimpaired controls. All of the participants had historical data of 2 to 4 three-dimensional T1 images and 2 to 6 annual cognitive evaluations over a follow-up period of 7 years. Tau topography was measured using Florzolotau(18F) PET. In the LOAD and TCP groups, we constructed tau or gray matter clusters covarying with the cognitive measurements. We used mediator analysis to explore the regional tau load as predictor, gray matter partitions as mediators, and significant cognitive test scores as outcomes. Longitudinal cognitive decline and cortical thickness degeneration pattern were analyzed using a linear mixed-effects model. RESULTS: The TCP group had longitudinal declines in nonexecutive domains. The deterministic factor predicting the short-term memory score in TCP was the hippocampal volume and not directly via the medial and lateral temporal tau load. These features formed the conceptual differences with LOAD. DISCUSSION: The biological properties of tau and the longitudinal cognitive-imaging trajectory support the conceptual distinction between TCP and LOAD. TCP represents one specific entity featuring salient short-term memory impairment, declines in nonexecutive domains, a slower gray matter degenerative pattern, and a restricted impact of tau.

CD20highCD138low tumor-infiltrating lymphocytes predominantly related to cytokine‒cytokine receptor interactions are associated with favorable outcomes in neuroblastoma patients.

Recent advances have revealed that the role of the immune system is prominent in the antitumor response. In the present study, it is aimed to provide an expression profile of tumor-infiltrating lymphocytes (TILs), including mature B cells, plasma cells, and their clinical relevance in neuroblastoma. The expression of CD20 and CD138 was analyzed in the Cangelosi786 dataset (n = 769) as a training dataset and in our cohort (n = 120) as a validation cohort. CD20 high expression was positively associated with favorable overall survival (OS) and event-free survival (EFS) (OS: P < 0.001; EFS: P < 0.001) in the training dataset, whereas CD138 high expression was associated with poor OS and EFS (OS: P < 0.001; EFS: P < 0.001) in both the training and validation datasets. Accordingly, a combined pattern of CD20 and CD138 expression was developed, whereby neuroblastoma patients with CD20highCD138low expression had a consistently favorable OS and EFS compared with those with CD20lowCD138high expression in both the training and validation cohorts (P < 0.0001 and P < 0.01, respectively). Examination of potential molecular functions revealed that signaling pathways, including cytokine‒cytokine receptor interactions, chemokine, and the NF-kappa B signaling pathways, were involved. Differentially expressed genes, such as BMP7, IL7R, BIRC3, CCR7, CXCR5, CCL21, and CCL19, predominantly play important roles in predicting the survival of neuroblastoma patients. Our study proposes that a new combination of CD20 and CD138 signatures is associated with neuroblastoma patient survival. The related signaling pathways reflect the close associations among the number of TILs, cytokine abundance and patient outcomes and provide therapeutic insights into neuroblastoma.

Analysis of early response to chemotherapy for non-Hodgkin's lymphoma by quantitative contrast-enhanced ultrasound: A prospective case-control crossectional study.

OBJECTIVE: To investigate the value of quantitative contrast-enhanced ultrasonography (CEUS) in assessing and predicting early therapy response of non-Hodgkin's lymphoma (NHL). METHODS: Fifty-six cases of NHL were studied using CEUS before and after three cycles of R-CHOP / CHOP. Quantitative parameters such as arrival time (ATM), time to peak (TTP), △T = TTP-ATM, area under the gamma curve (Area), curve gradient (Grad), wash-out time (WT), base intensity (BI), peak intensity (PI) and ΔI = PI-BI were compared between the lymphoma and normal lymph nodes before and at mid-treatment, respectively. Changes in quantitative CEUS parameters were also compared between complete response (CR) and incomplete response(non-CR) groups. Besides, the correlation analysis was performed between pretreatment PI and changes in quantitative parameters. RESULTS: After three cycles of R-CHOP/CHOP, S/L (P < 0.001), PI (P = 0.002), ΔI (P < 0.001), Grad (P < 0.001), and Area (P < 0.001) of NHL were significantly decreased. The CR group and non-CR group only differed in ATM before treatment. In contrast, there was no statistical difference in any of the parameters between the two groups at mid-treatment. Finally, a significant correlation was observed between pre-treatment PI and PI△% (r = 0.736, P < 0.001). CONCLUSIONS: CEUS is promising for the assessment of response of NHL to R-CHOP/CHOP. Intra-lesion perfusion changes take precedence over morphological changes suggesting treatment efficacy. Pre-treatment ATM values may help to suggest efficacy outcomes and pre-treatment PI values may be a valid predictor of lymphoma perfusion response.

Effectiveness of a health education program for people with dementia and their family caregivers: An intervention by nurse practitioners.

PURPOSE: This study assesses the effectiveness of a health education program on caregiving outcomes for people with dementia and their families. METHODS: This quasi-experimental study involved 250 people with dementia and their family caregivers. Behavioral problems in people with dementia were assessed using the Chinese version of the Cohen-Mansfield Agitation Inventory-community form. Family caregiver outcomes were measured using the Agitation Management Self-Efficacy Scale, Caregiver Preparedness Scale, Competence Scale, and Community Resource Awareness and Utilization Assessment. RESULTS: Following the intervention, the experimental group demonstrated significant improvements in terms of self-efficacy, preparedness, competence, and awareness and utilization of community resources among family caregivers. Additionally, the experimental group exhibited lower levels of behavioral problems among people with dementia. CONCLUSIONS: This study helped improve caregiving outcomes for people with dementia and their family caregivers. Therefore, outpatient healthcare providers can utilize these findings to enhance care for this population.

Antioxidant and Anti-Inflammatory Properties of Hydrolyzed Royal Jelly Peptide in Human Dermal Fibroblasts: Implications for Skin Health and Care Applications.

Hydrolyzed royal jelly peptide (RJP) has garnered attention for its health-promoting functions. However, the potential applications of RJP in skincare have not been fully explored. In this study, we prepared RJP through the enzymatic hydrolysis of royal jelly protein with trypsin and investigated its antioxidant and anti-inflammatory properties on primary human dermal fibroblasts (HDFs). Our results demonstrate that RJP effectively inhibits oxidative damage induced by H2O2 and lipid peroxidation triggered by AAPH and t-BuOOH in HDFs. This effect may be attributed to the ability of RJP to enhance the level of glutathione and the activities of catalase and glutathione peroxidase 4, as well as its excellent iron chelating capacity. Furthermore, RJP modulates the NLRP3 inflammasome-mediated inflammatory response in HDFs, suppressing the mRNA expressions of NLRP3 and IL-1ß in the primer stage induced by LPS and the release of mature IL-1ß induced by ATP, monosodium urate, or nigericin in the activation stage. RJP also represses the expressions of COX2 and iNOS induced by LPS. Finally, we reveal that RJP exhibits superior antioxidant and anti-inflammatory properties over unhydrolyzed royal jelly protein. These findings suggest that RJP exerts protective effects on skin cells through antioxidative and anti-inflammatory mechanisms, indicating its promise for potential therapeutic avenues for managing oxidative stress and inflammation-related skin disorders.

Prenatal High-Sucrose Diet Induced Vascular Dysfunction of Renal Interlobar Arteries in the Offspring via PPARγ-RXRg-ROS/Akt Signaling.

SCOPE: Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases; however whether maternal high-sucrose diet (HS) during pregnancy causes vascular damage in renal interlobar arteries (RIA) from offspring still keeps unclear. METHODS AND RESULTS: Pregnant rats are fed with normal drinking water or 20% high-sucrose solution during the whole gestational period. Swollen mitochondria and distributed myofilaments are observed in vascular smooth muscle cells of RIA exposed to prenatal HS. Maternal HS increases phenylephrine (PE)-induced vasoconstriction in the RIA from adult offspring. NG-Nitro-l-arginine (L-Name) causes obvious vascular tension in response to PE in offspring from control group, not in HS. RNA-Seq of RIA is performed to reveal that the gene retinoid X receptor g (RXRg) is significantly decreased in the HS group, which could affect vascular function via interacting with PPARγ pathway. By preincubation of RIA with apocynin (NADPH inhibitor) or capivasertib (Akt inhibitor), the results indicate that ROS and Akt are the vital important factors to affect the vascular function of RIA exposure to prenatal HS. CONCLUSION: Maternal HS during the pregnancy increases PE-mediated vasoconstriction of RIA from adult offspring, which is mainly related to the enhanced Akt and ROS regulated by the weakened PPARγ-RXRg.

Prenylated indole diketopiperazine alkaloids as phosphatase inhibitors from the marine-derived fungus Talaromyces purpureogenus.

Six previously undescribed prenylated indole diketopiperazine alkaloids, talaromyines A-F (1-6), were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic data including NMR, HR-ESI-MS, and electronic circular dichroism calculations, together with chemical analysis of hydrolysates. Compounds 1-5 represent the first example of spirocyclic indole diketopiperazines biosynthesized from the condensation of L-tryptophan and L-alanine. Compounds 2 and 4-5 showed selective inhibitory activities against phosphatases TCPTP and MEG2 with IC50 value of 17.9-29.7 µM, respectively. Compounds 4-5 exhibited mild cytotoxic activities against two human cancer cell lines H1975 and HepG-2.

Regional and temporal variations in COVID-19 cases and deaths in Ethiopia: Lessons learned from the COVID-19 enhanced surveillance and response.

BACKGROUND: The COVID-19 pandemic is one of the most devastating public health emergencies of international concern to have occurred in the past century. To ensure a safe, scalable, and sustainable response, it is imperative to understand the burden of disease, epidemiological trends, and responses to activities that have already been implemented. We aimed to analyze how COVID-19 tests, cases, and deaths varied by time and region in the general population and healthcare workers (HCWs) in Ethiopia. METHODS: COVID-19 data were captured between October 01, 2021, and September 30, 2022, in 64 systematically selected health facilities throughout Ethiopia. The number of health facilities included in the study was proportionally allocated to the regional states of Ethiopia. Data were captured by standardized tools and formats. Analysis of COVID-19 testing performed, cases detected, and deaths registered by region and time was carried out. RESULTS: We analyzed 215,024 individuals' data that were captured through COVID-19 surveillance in Ethiopia. Of the 215,024 total tests, 18,964 COVID-19 cases (8.8%, 95% CI: 8.7%- 9.0%) were identified and 534 (2.8%, 95% CI: 2.6%- 3.1%) were deceased. The positivity rate ranged from 1% in the Afar region to 15% in the Sidama region. Eight (1.2%, 95% CI: 0.4%- 2.0%) HCWs died out of 664 infected HCWs, of which 81.5% were from Addis Ababa. Three waves of outbreaks were detected during the analysis period, with the highest positivity rate of 35% during the Omicron period and the highest rate of ICU beds and mechanical ventilators (38%) occupied by COVID-19 patients during the Delta period. CONCLUSIONS: The temporal and regional variations in COVID-19 cases and deaths in Ethiopia underscore the need for concerted efforts to address the disparities in the COVID-19 surveillance and response system. These lessons should be critically considered during the integration of the COVID-19 surveillance system into the routine surveillance system.

Regulation of hepatocyte phospholipid peroxidation signaling by a Chinese patent medicine against psychological stress-induced liver injury.

BACKGROUND: Psychological stress is associated with various diseases including liver dysfunction, yet effective intervention strategies remain lacking due to the unrevealed pathogenesis mechanism. PURPOSE: This study aims to explore the relevance between BMAL1-controlled circadian rhythms and lipoxygenase 15 (ALOX15)-mediated phospholipids peroxidation in psychological stress-induced liver injury, and to investigate whether hepatocyte phospholipid peroxidation signaling is involved in the hepatoprotective effects of a Chinese patent medicine, Pien Tze Huang (PZH). METHODS: Restraint stress models were established to investigate the underlying molecular mechanisms of psychological stress-induced liver injury and the hepatoprotective effects of PZH. Redox lipidomics based on liquid chromatography-tandem mass spectrometry was applied for lipid profiling. RESULTS: The present study discovered that acute restraint stress could induce liver injury. Notably, lipidomic analysis confirmed that phospholipid peroxidation was accumulated in the livers of stressed mice. Additionally, the essential core circadian clock gene Brain and Muscle Arnt-like Protein-1 (Bmal1) was altered in stressed mice. Circadian disruption in mice, as well as BMAL1-overexpression in human HepaRG cells, also appeared to have a significant increase in phospholipid peroxidation, suggesting that stress-induced liver injury is closely related to circadian rhythm and phospholipid peroxidation. Subsequently, arachidonate 15-lipoxygenase (ALOX15), a critical enzyme that contributed to phospholipid peroxidation, was screened as a potential regulatory target of BMAL1. Mechanistically, BMAL1 promoted ALOX15 expression via direct binding to an E-box-like motif in the promoter. Finally, this study revealed that PZH treatment significantly relieved pathological symptoms of psychological stress-induced liver injury with a potential mechanism of alleviating ALOX15-mediated phospholipid peroxidation. CONCLUSION: Our findings illustrate the critical role of BMAL1-triggered phospholipid peroxidation in psychological stress-induced liver injury and provide new insight into treating psychological stress-associated liver diseases by TCM intervention.

Experimental Study of Interference in Calcitonin Testing: A Case Report and Literature Review.

BACKGROUND: Calcitonin (CT) is a sensitive serum marker of medullary thyroid carcinoma usually detected via immunoassays; however, its levels are easily disturbed by several endogenous factors. OBJECTIVE: The study aimed to discuss a case of suspected interference resulting in aberrant CT values and review previous reports of CT interference. METHODS: A female patient visited our clinic with a physical ultrasound examination showing a slightly enlarged thyroid gland with small nodules. She had elevated CT levels, inconsistent with the clinical presentation and other findings. We evaluated the results by retesting using the same platform, platform validation, multiplex dilution, Polyethylene Glycol (PEG) precipitation, heterophilic blocking tubes, and RET gene analysis. RESULTS: Retesting CT using the same platform confirmed the high value obtained. However, serial dilution of the sample produced nonlinear results, suggesting some interference. While PEG precipitation did not significantly reduce the CT level, incubating the sample in HBTs normalized the CT value, indicating interference from heterophilic antibodies. Gene sequencing revealed no RET mutations. CONCLUSION: In cases where elevated CT levels are inconsistent with clinical presentations and other findings, the laboratory technicians should communicate with clinicians, analyze the reasons for the inconsistent results, and use different methods to verify the results. Accurate testing provides realistic and reliable data for doctors and patients and helps to avoid unnecessary procedures.

Mechanistic Insights into the Excited-State Intramolecular Proton Transfer (ESIPT) Process of 2-(2-Aminophenyl)naphthalene.

The 2-(2-aminophenyl)naphthalene molecule attracted much attention due to excited-state intramolecular proton transfer (ESIPT) from an amino NH2 group to a carbon atom of an adjacent aromatic ring. The ESIPT mechanisms of 2-(2-aminophenyl)naphthalene are still unclear. Herein, the decay pathways of this molecule in vacuum were investigated by combining static electronic structure calculations and nonadiabatic dynamics simulations. The calculations indicated the existence of two stable structures (S0-1 and S0-2) in the S0 and S1 states. For the S0-1 isomer, upon excitation to the Franck-Condon point, the system relaxed to the S1 minimum quickly, and then there exist four decay pathways (two ESIPT ones and two decay channels with C atom pyramidalization). In the ESIPT decay pathways, the system encounters the S1S0-PT-1 or S1S0-PT-2 conical intersection, which funnels the system rapidly to the S0 state. In the other two pathways, the system de-excited from the S1 to the S0 state via the S1S0-1 or S1S0-2 conical intersection. For the S0-2 structure, the decay pathways were similar to those of S0-1. The dynamics simulations showed that 75 and 69% of trajectories experienced the two ESIPT conical intersections for the S0-1 and S0-2 structures, respectively. Our simulations showed that the lifetime of the S1 state of S0-1 (S0-2) is estimated to be 358 (400) fs. Notably, we not only found the detailed reaction mechanism of the system but also found that the different ground-state configurations of this system have little effect on the reaction mechanism in vacuum.

MODY Probability Calculator Is Suitable for MODY Screening in China: A Population-based Study.

Context: Selecting appropriate individuals for genetic testing is essential due to the optimal treatment for maturity-onset diabetes of the young (MODY). However, how to effectively screen for MODY in China remains unclear. Objective: To validate the performance of current screening strategies in selecting patients with MODY based on a nationwide type 2 diabetes cohort. Methods: A panel of 14 MODY genes was analyzed from 1911 type 2 diabetes patients who were ages 15 to 35 years. Variants were evaluated according to the American College of Medical Genetics and Genomics guidelines. Based on this cohort, we simulated the 2 most frequently used screening strategies, including the traditional MODY criteria and the MODY probability calculator (MPC), to assess their ability to select patients with MODY. Results: From a total of 1911 participants, 42 participants harbored pathogenic/likely pathogenic variants. The performance of the traditional criteria was sensitivity: 19.0%, specificity: 72.9%, positive predictive value (PPV): 1.6%, and missing rate: 81.0%. The optimal cut-off for MPC was 40.7%. Based on this cut-off value, the performance was sensitivity: 54.8%, specificity: 81.0%, PPV: 6.1%, and missing rate: 45.2%. Moreover, hemoglobin A1c, insulin treatment, and family history of diabetes have poor discrimination between MODY and young-onset type 2 diabetes. Conclusion: The MPC is better than traditional criteria in terms of both sensitivity and PPV. To ensure more MODY patients benefit from optimal treatment, we therefore suggest that routine genetic testing be performed on all type 2 diabetes patients who are between the ages of 15 and35 years and have MPC probability value over 40.7%.

Reference intervals for thyroid function from the fifth to seventh day of life in twin-pregnancy preterm neonates: an 8-year retrospective study.

PURPOSE: The immature and developing hypothalamic-pituitary-thyroid axis leads to different levels of thyroid function in twin neonates, including free thyroxine (FT4), free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) levels. No reference intervals for twins have been established until now. To compensate for this lack, we collected data and established this standard across different gestational ages (GAs) and sexes. METHODS: A total of 273 pairs of neonates admitted to the NICU in Southeast China from 2015 to 2022 were included. Each pair was divided into Neonate A (relatively heavy birth weight (BW)) and Neonate B (relatively light BW). Their thyroid functions were analyzed to establish reference intervals and comparisons were made stratified by GA and sex. RESULTS: The FT3, FT4, and TSH reference intervals in twin neonates with a GA of 26-36 weeks were as follows: Neonate A and B: 3.59 ± 0.99 and 3.57 ± 1.00 pmol/L; Neonate A and B: 17.03 ± 5.16 and 16.77 ± 5.29 pmol/L; and Neonate A and B: 4.097 ± 3.688 and 4.674 ± 4.850 mlU/L, respectively. There were significant differences between serum FT3 and FT4 reference intervals and GA (p < 0.05). The serum FT3 and FT4 reference intervals for male neonates were lower than those for female neonates in the 29-32-week group (p < 0.05). CONCLUSION: This was the first study, to our knowledge, to establish reference intervals for thyroid function in twin neonates from the fifth to seventh day of life, which will be beneficial for the diagnosis and management of congenital hypothyroidism.

Exploring the origin of a unique mutant allele in twin-tail goldfish using CRISPR/Cas9 mutants.

Artificial selection has been widely applied to genetically fix rare phenotypic features in ornamental domesticated animals. For many of these animals, the mutated loci and alleles underlying rare phenotypes are known. However, few studies have explored whether these rare genetic mutations might have been fixed due to competition among related mutated alleles or if the fixation occurred due to contingent stochastic events. Here, we performed genetic crossing with twin-tail ornamental goldfish and CRISPR/Cas9-mutated goldfish to investigate why only a single mutated allele-chdS with a E127X stop codon (also called chdAE127X)-gives rise to the twin-tail phenotype in the modern domesticated goldfish population. Two closely related chdS mutants were generated with CRISPR/Cas9 and compared with the E127X allele in F2 and F3 generations. Both of the CRISPR/Cas9-generated alleles were equivalent to the E127X allele in terms of penetrance/expressivity of the twin-tail phenotype and viability of carriers. These findings indicate that multiple truncating mutations could have produced viable twin-tail goldfish. Therefore, the absence of polymorphic alleles for the twin-tail phenotype in modern goldfish likely stems from stochastic elimination or a lack of competing alleles in the common ancestor. Our study is the first experimental comparison of a singular domestication-derived allele with CRISPR/Cas9-generated alleles to understand how genetic fixation of a unique genotype and phenotype may have occurred. Thus, our work may provide a conceptual framework for future investigations of rare evolutionary events in domesticated animals.

Zonular instability-associated morphologic features in eyes with primary angle closure disease using the swept-source anterior segment - optical coherence tomography system.

BACKGROUND: This study aims to investigate the morphologic features of the crystalline lens in Primary Angle Closure Disease (PACD) patients with zonular instability during cataract surgery using the swept-source CASIA 2 Anterior Segment-Optical Coherence Tomography (AS-OCT) system. METHODS: A total of 398 eyes (125 PACD eyes with zonular instability, 133 PACD eyes with zonular stability, and 140 cataract patient controls) of 398 patients who underwent cataract surgery combined or not glaucoma surgery between January 2021 and January 2023 were enrolled. The crystalline lens parameters were measured by CASIA2 AS-OCT. Then, logistic regression was performed to evaluate the risk factors associated with zonular instability. RESULTS: The results revealed that PACD eyes had a more anterior lens equator position, a steeper anterior curvature of lens, shorter Axial Length (AL), shallower Anterior Chamber Distance (ACD), higher Lens Vault (LV) and thicker Lens Thickness (LT), when compared to eyes in the cataract control group. Furthermore, PACD eyes in the zonular instability group had steeper front R, front Rs and Front Rf, flatter back Rf, thicker lens anterior part thickness, higher lens anterior-to-posterior part thickness ratios, shallower ACD, and greater LV, when compared to PACD eyes with zonular stability. The logistic regression analysis, which was adjusted for age and gender, revealed that zonular instability was positively correlated with anterior part thickness, lens anterior-to-posterior part thickness ratio, and LV, but was negatively correlated with lens anterior radius and ACD. CONCLUSION: Steeper anterior curvature, increased lens anterior part thickness, higher anterior-to-posterior part thickness ratio, shallower ACD, and greater LV are the anatomic features of PACD eyes associated with zonular instability.

Lowest Glucagon/Highest C-Peptide in Oral Glucose Tolerance Test: Clinical Utility in Monitoring Glucose Control in Type 2 Diabetes Mellitus.

Purpose: Understanding factors that influence blood glucose levels in patients with type 2 diabetes mellitus (T2DM) is crucial for managing hyperglycemia. Currently, there is no standardized interpretation method for glucagon levels in oral glucose tolerance test (OGTT). This study aims to assess the relationship between the lowest glucagon/highest C-peptide ratio (Lglc/Hcp) in OGTT and glucose control levels in T2DM. Patients and Methods: Clinical data from 120 patients with T2DM were examined to compare the correlations of Lglc/Hcp and other pancreatic islet function-associated indices with fasting blood glucose (G0), glucose at 120 minutes in OGTT (G120), hemoglobin A1c (HbA1c), and the area under the glucose curve in OGTT (AUCglu). Additionally, the study investigated difference in Lglc/Hcp between patient groups based on the highest blood glucose levels (Hglu) in OGTT (Hglu ≥ 16.7 mmol/L vs Hglu < 16.7 mmol/L). Results: The generalized linear model suggested that Lglc/Hcp significantly correlated with G0 (B = 0.85, P < 0.001), G120(B = 1.46, P < 0.001), HbA1c (B = 0.67, P < 0.001), and AUCglu (B = 3.46, P < 0.001). This correlation surpassed C-peptide and glucagon-related parameters, even after adjusting for confounding factors. Furthermore, Lglc/Hcp was notably higher in patients with Hglu ≥ 16.7 mmol/L compared to those with Hglu < 16.7 mmol/L (Z = -3.71, p < 0.001). Conclusion: Lglc/Hcp in OGTT closely relates to blood glucose control in patients with T2DM, potentially reflecting the overall pancreatic islet function in regulating glucose levels. Moreover, inhibiting glucagon secretion may be a crucial consideration for patients requiring insulin treatment.

Bioinformatics and LC-QTOF-MS based discovery of pharmacodynamic and Q-markers of Pitongshu against functional dyspepsia.

ETHNOPHARMACOLOGICAL RELEVANCE: Pitongshu (PTS) is a clinically effective empirical formula for the treatment of FD. The efficacy and safety of PTS have been demonstrated in randomized, controlled, double-blind trials, but there is a lack of understanding of the systematic evaluation of the efficacy of PTS and its material basis. OBJECTIVE: To investigate the efficacy of PTS in Functional dyspepsia (FD) mice and possible Q-markers. METHOD: In this study, we used "irregular feeding + chronic unpredictable chronic stimulation" to establish a mice model of FD with hepatogastric disharmony. The efficacy of PTS was assessed from hair condition, behavioral, pain, gastrointestinal function, and serum 5-HT, GAS, MTL levels in mice by instillation of different doses of PTS. In addition, the composition of drugs in blood was analyzed by LC-QTOF-MS and potential Q-markers were selected by combining network pharmacology, molecular docking and actual content. RESULT: Our study showed that different doses of PTS increased pain threshold and writhing latency, decreased the number of writhings, increased gastric emptying rate and small intestinal propulsion rate, decreased total acidity of gastric contents and gastric acid secretion, and increased serum levels of 5-HT, GAS, and MTL in mice to different degrees. Enrichment analysis showed that PTS may be anti-FD through multiple pathways such as Serotonergic synapse, thyroid hormone signaling pathway, cholinergic synapse, and dopaminergic synapse. In addition, potential active ingredient substances were explored by LC-QTOF-MS combined with bioinformatics. Combined with the actual contentselected six constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol, possible as Q-markers. CONCLUSION: PTS may exert its anti-FD effects through multi-component, multi-target and multi-pathway". Constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol may be the Q-markers of its anti-FD effects.

The use of individual-based FDG-PET volume of interest in predicting conversion from mild cognitive impairment to dementia.

BACKGROUND: Based on a longitudinal cohort design, the aim of this study was to investigate whether individual-based 18F fluorodeoxyglucose positron emission tomography (18F-FDG-PET) regional signals can predict dementia conversion in patients with mild cognitive impairment (MCI). METHODS: We included 44 MCI converters (MCI-C), 38 non-converters (MCI-NC), 42 patients with Alzheimer's disease with dementia, and 40 cognitively normal controls. Data from annual cognitive measurements, 3D T1 magnetic resonance imaging (MRI) scans, and 18F-FDG-PET scans were used for outcome analysis. An individual-based FDG-PET approach was applied using seven volumes of interest (VOIs), Z transformed using a normal FDG-PET template. Hypometabolism was defined as a Z score < -2 of regional standard uptake value ratio. For the longitudinal cognitive test scores, generalized estimating equations were used. A linear mixed-effects model was used to compare the temporal impact of cortical hypometabolism and cortical thickness degeneration. RESULTS: The clinical follow-up period was 6.6 ± 3.8 years (range 3.1 to 16.0 years). The trend of cognitive decline could differentiate MCI-C from MCI-NC after 3 years of follow-up. In the baseline 18F-FDG-PET scan of the patients with MCI, medial temporal lobe (MTL; 94.7% sensitivity, 80.5% specificity) and posterior cingulate cortex (PCC; 89.5% sensitivity, 73.1% specificity) hypometabolism predicted conversion with high accuracy. 18F-FDG-PET hypometabolism preceded dementia conversion at an interval of 3.70 ± 1.68 years and was earlier than volumetric changes, with the exception of the MTL. CONCLUSIONS: Our finding supports the use of individual-based 18F-FDG-PET analysis to predict MCI conversion to dementia. Reduced FDG-PET metabolism in the MTL and PCC were strongly associated with future cognitive decline in the MCI-C group. Changes in 18F-FDG-PET occurred 1 to 8 years prior to conversion to dementia. Progressive hypometabolism in the PCC, precuneus and lateral temporal lobe, but not MTL, preceded MRI findings at the MCI stage.

New Antibacterial Peptaibiotics against Plant and Fish Pathogens from the Deep-Sea-Derived Fungus Simplicillium obclavatum EIODSF 020.

Bacterial diseases could severely harm agricultural production. To develop new antibacterial agents, the secondary metabolites of a deep-sea-derived fungus Simplicillium obclavatum EIODSF 020 with antibacterial activities against plant and fish pathogens were investigated by a bioassay-guided approach, which led to the isolation of 11 new peptaibiotics, simplicpeptaibs A-K (1-11). They contain 16-19 residues, including ß-alanine, tyrosine, or tyrosine O-sulfate, that were rarely present in peptaibiotics. Their structures were elucidated by spectroscopic analyses (NMR, HRMS, HRMS2, and ECD) and Marfey's method. The primary and secondary structures of novel sulfated peptaibiotic 9 were reconfirmed by single-crystal X-ray diffraction analysis. Genome sequencing of S. obclavatum EIODSF 020 allowed the detection of a gene cluster encoding two individual NRPSs (totally containing 19 modules) that was closely related to simplicpeptaib biosynthesis. Antibacterial investigations of 1-11 together with the previously isolated linear and cyclic peptides from this strain suggested the antibacterial property of this fungus was attributed to the peptaibiotics and cyclic lipopeptides. Among them, compounds 4, 6, 7, and 9 showed significant activity against the tobacco pathogen Ralstonia solanacearum or tilapia pathogens Streptococcus iniae and Streptococcus agalactiae. The antibacterial activity of 6 against R. solanacearum could be enhanced by the addition of 1% NaCl. The structure-bioactivity relationship of simplicpeptaibs was discussed.